How the cytosol‐to‐membrane translocation kinetics and signaling of PKCγ are dysregulated in the neurodegenerative spinocerebellar ataxia type14 (SCA14)

The spinocerebellar ataxia type 14 (SCA14) is an autosomal neurodegeneration disease that is clinically characterized by the progressive ataxia of gait accompanied by slurred speech and abnormal eye movements. These symptoms are linked to the loss of Purkinje cells leading to cerebellar neurodegeneration. The onset age of this disease is in the range of 33–43 years. The MRI results clearly show the atrophy of cerebellum and autopsy results indicates the reduction in number of Purkinje cells as well the size and complexity of their dendritic arbor. Observations in Purkinje cells link PKCγ to the SCA14 disease and its gene PRKCG is now widely recognized as a disease‐causing gene. PKCγ. The PKCγ is a brain specific molecule and is highly expressed in cPCs. Observations also show that PKCγ link to SCA14 is established more through gain‐of‐function and in fact both positive and negative regulation of PKCγ expression and activity could result in the changes in number, size and complexity of dendritic arbors in Purkinje cells. Here, we investigate the question that why the membrane residence time of PKCγ is decreased in SCA14 compared to wildtype (WT) cPCs. We explore this question by proposing two signaling models for PKCγ; First model describes the signaling mechanism of how could the activity of WT PKCγ be regulated in cPCs, whereas the second model shows the signaling of mutant PKCγ in SCA14 associated cPCs. Both these models show that in response to extracellular stimuli‐induced depolarization at membrane, both PKCγ and DGKγ translocate to the membrane. Our results also indicate that for same set of parameters the membrane residence time of PKCγ is shorter compared to WT molecule. These results explain that membrane residence time of PKCγ is regulated by DAG and the translocated molecule returns to cytosol as the DAG levels decrease. These results suggest that even though all the kinetic parameters are same in WT & mutant models the residence time of PKCγ is reduced in mutant model due to reduced signaling. This study shows that for the same strength of extracellular signal the membrane life time of mutant PKCγ is decreased due to constitutively active mutant PKCγ molecule in cytosol. This cytosolic molecule in turn, leads to the phosphorylation and activation of DGKγ molecule inside cytosol. Thus, mutant model explains that when both the DAG effector molecules are found in their active states in cytosol their interactions in membrane compartment are reduced thus, reducing the residence time of PKCγ molecule in membrane compartment in mutant model. Support or Funding Information Privately Funded